PROJECTSUMMARY/ABSTRACT Schizophreniaisamongthemostsevereandburdensomemedicalconditionsworldwide,yetthebrainalterations thatleadtothesymptomsofschizophreniaremainunknown.ThisK23applicationpresentsaresearchandtraining programthatwillsupporttheapplicantonapathtowardsbecominganNIH-?fundedindependentinvestigatorfocused onunderstandingtheneurobiologyofschizophreniaandrelatedpsychoticdisorders.Theactivitiesinthisapplication buildonthecandidate?spriortrainingandaresetinaresource-?richenvironmentthatwillfosterherdevelopmentof expertisein1)applicationofMRSandadvancedMRIneuroimagingmethodologies;2)physician-?scientistapproachesto studyingpathophysiologyinpatientswithschizophrenia;3)neurocircuitryandsystemsneuroscienceperspectiveson hippocampuspathologyinpsychoticdisorders;and4)responsibleconductofresearch.Theoverarchinggoalofthe researchtobecarriedoutinthisapplicationistotakefindingsfromanimalmodelsofschizophrenia,whichwere motivatedbyoriginalresearchinpatientswiththedisorder,backtotheclinicalsettinginordertodeterminewhether thebraincircuitalterationsobservedintheanimalmodelsareobservableinhumanpatients.Specifically,findingsinthe prenatalmethylazoxymethanolacetate(MAM)rodentmodel,whichwasdevelopedtomodelthealterationsin dopaminefunctionseeninpatientswithschizophrenia,suggesthyperactivityoftheventral(anterior)hippocampusmay increaseitsglutamatergicoutputtotheventralstriatumandlead,viaventralpallidalandotherGABAergicprojectionsto theventralmidbrain,todisinhibitedfiringofdopamineneurons.Inaddition,aconvergenceofseveralpostmortemand invivoimagingfindingsinpatientssuggeststhatabnormalGABAergicactivityinthehippocampusmayfurther compoundhippocampalglutamatergicoverdrive.Thisprojectwilldirectlytesttherelationshipsamongthese neurochemicalalterationsinindividualmedication-?freepatientswithschizophreniausingsophisticatedmagnetic resonanceimagingmethods.Ifthisnon-?invasive,multimodalimagingparadigmprovidesevidencetorelatehippocampal GABAandglutamateabnormalitiestodopaminesystemdysfunctioninpatientswithschizophrenia,itwouldhave importantimplicationsforourunderstandingofthebrainbasesofschizophrenia,andwouldgenerateanovel multimodalimagingparadigmfortestingnewmolecular,anatomical,andcircuit-?modulatingtargetsfortreatmentof thisdevastatingillness.